MHC class I expression is subject to both tissue-specific and hormonal regulatory mechanisms. Expression of MHC class I is dynamically regulated in response to a variety of stimuli. Agents such as TNF and interferon are well known inducers of class I transcription. In contrast, thyroid stimulating hormone (TSH) specifically reduces class I gene transcription in thyrocytes; this down-regulation is cAMP-mediated. Whereas previous studies in the laboratory have focused on the mechanisms of TSH-mediated repression, recent studies are examining the molecular basis of interferon-mediated induction through the transcriptional co-activator CIITA. The CIITA co-activator is essential for transcriptional activation of MHC class II genes and mediates enhanced MHC class I transcription. Class I promoter activation by CIITA requires both the downstream core promoter and upstream sequences. Activation is absolutely dependent on the upstream CRE, located between -100 and -107 bp, but is further enhanced by a series of upstream sequence elements. Interestingly, the DNA sequence requirements for CIITA mediated activation are distinct from those of constitutive transcription. Furthermore, the transcription factor requirements for CIITA activation are also distinct from those of constitutive transcription: constitutive transcription requires TAFII250 whereas CIITA activation does not.Levels of expression also vary widely among tissues, with the highest levels of class I occurring in the lymphoid compartment, in T cells and B cells. While the high class I expression in B cells is known to involve the CIITA-containing B cell enhanceosome, the molecular basis for high constitutive class I expression in T cells has not been explored. T cell specific genes, such as T cell receptor genes, are regulated by a T cell enhanceosome consisting of RUNX1, CBF, LEF1 and Aly. In this report, we demonstrate that MHC class I gene expression is enhanced by the T cell enhanceosome and results from a direct interaction of the RUNX1-containing complex with the class I gene in vivo. T cell enhanceosome activation of class I transcription is synergistic with interferon- (IFN mediated activation and targets response elements distinct from those targeted by IFN These findings provide a molecular basis for the high levels of MHC class I in T cells.